WNV is the leading cause of domestically acquired arboviral disease in the United States. In addition to the acute neuroinvasive syndromes and persistent motor deficits, patients that recover from WN- fever (WNF) and WN neuroinvasive disease (WNND) experience significant long-term cognitive sequelae, including high rates of memory impairment and abnormalities in executive function. While improved survival rates from WNND (~91%) have led to rising numbers of patients currently living with these impairments, few studies have addressed underlying mechanisms responsible for these deficits. To address this, we have developed a new murine model of recovery from intracranial infection with a mutant WNV (WNV-NS5-E218A), leading to uniform infection across CNS regions and measurable spatial learning deficits that persist after viral clearance. Using this model we have traced learning defects to hippocampal pathology including CNS tissue resident memory CD8 T cells (Trm), microglial activation and altered neurogenesis within this brain region. Microarray analyses of differentially expressed mRNAs within the hippocampi of mice with neurocognitive deficits revealed increased expression of a variety of immune molecules expressed by Trm (CD103, CD69, IFITM3), and those known to drive microglial effects on synaptic modeling and neurogenesis (complement proteins C1q and C3), and caspase-1, which drives expression of interleukin(IL)-1. In preliminary studies, Trm are CCR2+IFN-?+ and WNV- recovered IFN-?- and IFN-?R- deficient mice do not display learning defects. Activated microglia and defects in neurogenesis within the subgranular zone (SGZ) of the dentate gyrus, but not the subventricular zone (SVZ), were found to persist long after clearance of replicating virus. Moreover, microglia phagocytosis of synapses was observed to occur via a complement-mediated process. We hypothesize that innate immune responses of hippocampal microglia after WNV infection are driven by Trm and contribute to spatial learning defects via their effects on synaptic elimination and neurogenesis. To test these hypotheses we will 1) Define the role of Trm-derived IFN-? in microglia activation and neurocognitive dysfunction during recovery from WNND, 2) Define the innate immune role of microglia in neural correlates of spatial memory during recovery from WNND; and 2) Determine the role of IL-1R1 signaling in microglial modulation of synapse elimination and neurogenesis in the WNV-recovered CNS.